While considerable progress has been made in characterizing the mechanisms that regulate CD4+ T cell responses to some acute infections, knowledge of the response to chronic infections of the gastrointestinal tract remains elusive. The overall goal of this research plan is to directly test the requirements for generating and maintaining a protective CD4+ T cell response during a chronic gastrointestinal infection with an important pathogen. A definitive study of this nature is complicated by two major issues in the field: 1) the relatively low frequency of CD4+ T cells with unique T cell antigen receptors (TCRs) recognizing specific pathogen-derived antigens makes the cells difficult to detect and 2) the lack of relevant mouse models that accurately reproduce human infection. These issues will be overcome by employing a cutting edge enrichment method to isolate and characterize the CD4+ T cells specifically responding to a chronic Salmonella infection in vivo. The central hypothesis of this application is that chronic, localized infection generates highly differentiated multifunctional CD4+ T cells that control pathogen burden and prevent disease by secreting macrophage-activating (interferon-3/tumor necrosis factor-1) and growth promoting (interleukin-2) lymphokines. Therefore, my specific aims are designed to address 1) which CD4+ T cell subset is capable of providing the best immune protection to Salmonella and 2) if repeated TCR stimulation increases the cytokine production capacity of responding T cells. This proposal supports the mission of the NIDDK by focusing on CD4+ T cell responses that are critical for controlling the gastrointestinal pathogen Salmonella enterica and could provide useful information on how to develop a more effective vaccine.